Activation of kappa opioid receptors (KOR) in humans elicits dysphoria, and KOR activation by agonists or by stress-induced dynorphin release in rodents produces reinstatement of drug seeking. The dysphoric/aversive effects of dynorphin/KOR system activity have been linked to increased cocaine self-administration, and cause reinstatement of cocaine seeking behaviors. While many reports of KOR dependent regulation of cocaine, morphine, and alcohol seeking exist, there are very few studies examining the role and mechanisms of stress-induced dynorphin-KOR activity on nicotine reinstatement. Despite recent efforts, nicotine use is at an all time high, is responsible for millions of deaths each year and remains one of the most difficult drugs to quit. The neural networks and cellular-molecular mechanisms responsible for KOR-dependent nicotine reinstatement are not understood. Given nicotine's diverse pharmacological profile and interaction within multiple circuits, understanding how dynorphin neural circuits and KOR activation causes nicotine reinstatement will provide novel, valuable, and important insights and suggest new therapeutic approaches to the treatment and prevention of stress-related nicotine relapse. While evidence shows a key role for KOR-dependent inhibition in ventral tegmental (VTA) nucleus Accumbens (NAc) circuits, recent evidence has strongly implicated dynorphin activation of p38 MAPK in the serotonergic dorsal raphe nucleus (DRN) as required for KOR-dependent reinstatement and aversion. The role of each pathway in nicotine reinstatement is not known, so we propose to methodically dissect how activation of KOR, either by stress-induced dynorphin, optogenetic modulation of dynorphin/CRF release, or systemic administration of a selective KOR agonist, results in reinstatement of nicotine conditioned place preference. To accomplish this we propose the following Aims using an array of multidisciplinary approaches: 1) to determine the role of dynorphin/KOR activity in serotonergic circuits as necessary and sufficient for stress-induced nicotine preference using viral rescue ("gain of function"), in vivo pharmacology, and mouse genetics to assess KOR in circuits mediating stress-induced and dynorphin/KOR-mediated reinstatement of nicotine preference. 2) to measure the effects of p38 MAPK activation in circuits required for stress-induced reinstatement of nicotine preference. 3) To use a novel mouse line coupled with optogenetic approaches to dissect dynorphinergic neural inputs into key sites of KOR action mediating reinstatement of nicotine preference. The proposed studies would test our central hypothesis that stress and KOR-induced reinstatement of nicotine reward is mediated as consequence of dynorphin-KOR-dependent activation of downstream signaling pathways in selected neural circuits.

Public Health Relevance

Stress has protective and motivational components yet repeated uncontrollable stress exposure increases the risks for mood disorders and nicotine addiction. Tobacco related deaths top 400,000 in US annually and the biological mechanisms underlying these effects need to be explored in order to provide for better treatments for nicotine addiction. Activation of the dynorphin/kappa opioid systems in brain has been shown to encode the dysphoric effects of stress and reinstates nicotine seeking, so the outcomes of the proposed studies would have direct impact on determining how stress modulates nicotine reward and offer potentially novel therapeutic strategies for nicotine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Sorensen, Roger
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Washington University
Schools of Medicine
Saint Louis
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Chang, Steven D; Bruchas, Michael R (2014) Functional selectivity at GPCRs: new opportunities in psychiatric drug discovery. Neuropsychopharmacology 39:248-9
Al-Hasani, Ream; McCall, Jordan G; Foshage, Audra M et al. (2013) Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism. Neuropsychopharmacology 38:2484-97
Al-Hasani, Ream; McCall, Jordan G; Bruchas, Michael R (2013) Exposure to chronic mild stress prevents kappa opioid-mediated reinstatement of cocaine and nicotine place preference. Front Pharmacol 4:96